Schuh Lea, Loos Carolin, Pokrovsky Daniil, Imhof Axel, Rupp Ralph A W, Marr Carsten
Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany; Department of Mathematics, Technical University of Munich, Garching 85748, Germany.
Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany; Department of Mathematics, Technical University of Munich, Garching 85748, Germany; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell Syst. 2020 Dec 16;11(6):653-662.e8. doi: 10.1016/j.cels.2020.11.003. Epub 2020 Dec 8.
DNA replication during cell division leads to dilution of histone modifications and can thus affect chromatin-mediated gene regulation, raising the question of how the cell-cycle shapes the histone modification landscape, particularly during embryogenesis. We tackled this problem by manipulating the cell cycle during early Xenopus laevis embryogenesis and analyzing in vivo histone H4K20 methylation kinetics. The global distribution of un-, mono-, di-, and tri-methylated histone H4K20 was measured by mass spectrometry in normal and cell-cycle-arrested embryos over time. Using multi-start maximum likelihood optimization and quantitative model selection, we found that three specific biological methylation rate constants were required to explain the measured H4K20 methylation state kinetics. While demethylation is essential for regulating H4K20 methylation kinetics in non-cycling cells, demethylation is very likely dispensable in rapidly dividing cells of early embryos, suggesting that cell-cycle-mediated dilution of H4K20 methylation is an essential regulatory component for shaping its epigenetic landscape during early development. A record of this paper's transparent peer review process is included in the Supplemental Information.
细胞分裂过程中的DNA复制会导致组蛋白修饰的稀释，从而可能影响染色质介导的基因调控，这就引发了一个问题：细胞周期如何塑造组蛋白修饰格局，尤其是在胚胎发育过程中。我们通过在非洲爪蟾胚胎发育早期操纵细胞周期并分析体内组蛋白H4K20甲基化动力学来解决这个问题。随着时间的推移，通过质谱法测量正常和细胞周期停滞胚胎中未甲基化、单甲基化、二甲基化和三甲基化组蛋白H4K20的全局分布。使用多起点最大似然优化和定量模型选择，我们发现需要三个特定的生物学甲基化速率常数来解释所测量的H4K20甲基化状态动力学。虽然去甲基化对于调节非循环细胞中的H4K20甲基化动力学至关重要，但在早期胚胎的快速分裂细胞中去甲基化很可能是不必要的，这表明细胞周期介导的H4K20甲基化稀释是早期发育过程中塑造其表观遗传格局的一个重要调控成分。本文透明同行评审过程的记录包含在补充信息中。
